Abstract: Worldwide, stroke and dementia account for half of all neurological disorders. Vascular cognitive impairment and dementia (VCID) is the second common cause of dementia. The key feature of VCID is diffuse white mater lesions (WML), detected as white matter hyperintensities (WMHs) on MRI scans. The neurological pathology of WMHs includes blood brain barrier disruption, myelin loss, axonal disruption, and astrogliosis. It is well established that hypertension and arteriosclerosis stenosis are the most significant risk factors for dementia epidemics. Currently, there are no therapies for symptomatic treatment of VCID and the underlying molecular and cellular mechanisms for cognitive deficits are not well understood. Associated with neurovascular decline is diminished nitric oxide (NO) signaling in neurons, vascular cells and innate immune cells providing one possible mechanism contributing to vascular dysfunction, WMH and dementia. We recently identified cytochrome b5 reductase 3 (Cyb5R3) as a soluble guanylyl cyclase (sGC) heme iron reductase in vascular smooth muscle, which reverses sGC oxidation (Fe3+?Fe2+) during oxidative stress to preserve NO signaling needed for vascular relaxation. In the human population, over 40 genetic polymorphisms in Cyb5R3 have been identified. Of particular interest is the missense variant at position 117 of the soluble protein or position 150 of the membrane protein, wherein the amino acid threonine is substituted for a serine residue. This is a high frequency genetic variant in individuals with African Ancestry (23% minor allele frequency) and found in less than 1% of any other race. Using a bilateral carotid artery stenosis model which mimics many features of vascular- related dementia, we will test if 1) mice carrying the T117S variant show accelerated neurovascular decline in response to VCID and 2) if sGC modulator therapies reverse the complications associated with VCID.